Arylhydrazones 5,6,7,8-tetrahydroquinoline-2,5 having cardiotonic activity

 

(57) Abstract:

Usage: as a drug, possess cardiotonic activity. The inventive compound f-ly 1, where if X is a CN-group, R1=R2=CH3, R3=C6H5(1A); R1=R2=H, R3=C6H5(1B); R1=R2=H, R3=C6H5(1B); R1=H, R2=R3=C6H5(1G) if X IS CONH2group, R1=R2=CH3, R3=C6H5(1D). R1=R2=H, R3=C6H5(1C). table 1.

The invention relates to the field of chemistry compounds quinoline series and applies a previously undescribed bioactive chemical compounds arylhydrazones 5, 6, 7, 8-tetrahydropyridine-2, 5 the General formula

(1) where, if X is CN-group,

R1= R2= CH3, R3= C6H5(Ia);

R1= R2= H, R3= C6H5(IB);

R1= R2= H, R3= C6F5(IB);

R1= H, R2= R3= C6H5(Iك);

if X is CONH2group

R1= R2= CH3, R3= C6H5(Ia);

R1= R2= H, R3= C6H5(S)Chornyi analogues of the claimed compounds are derivatives 5, 6, 7, 8-tetrahydroquinoline-2,5 following formula , but on the biological activity of these compounds information in the literature are missing.

In a series of derivatives of tetrahydroquinoline currently unknown compounds with cardiotonic activity.

Currently, a number of cardiotonic derived from their chemical structures of substituted pyridine-2 cycle, which leads to the existence of cardiotoniceski properties, there are two drug - aminon, milrinone [3 - 4 - 5] . They are applied in clinical practice. The most effective of these is milrinone - 3-cyanate-5-(pyridinyl-4)-6-methylpyridin-2 formula AND,

(A) which is selected by the authors as a pharmacological analogue of the claimed compounds. Milrinone used for the treatment of chronic heart failure.

However its relatively low cardiotonic activity.

The purpose of the invention is new derivatives of tetrahydroquinoline series containing substituted pyridine 2-cycle.

This goal is achieved by the chemical structure of the new arylhydrazones 5, 6, 7, 8-tetrahydroquinoline-2,5 General formula I.

The claimed link which when heated in dimethyl sulfoxide and dimethylformamide and insoluble in non-polar solvents.

The method of obtaining compounds of General formula I based on the known reaction of condensation of arylhydrazines with carbonyl compounds [7] .

The claimed compounds I are obtained by interaction of derivatives 5, 6, 7, 8-tetrahydroquinoline-2,5 General formula II, where R1, R2and X have the above meanings, with arylhydrazines General formula III, where R3have the above meanings, in the environment of glacial acetic acid in the temperature range from 30aboutC to the boiling temperature of the reaction mass according to the scheme:

The structure of the claimed compounds is confirmed by elemental analysis and spectral data (see tab. 1 and 2).

The original connection and the retrieval method described in the literature [1, 2] .

The following examples illustrate obtaining the claimed compounds.

P R I m e R 1. Getting 5-phenylhydrazone 3-cyano-7, 7-dimethyl-5, 6, 7, 8-tetrahydroquinoline-2,5 (Ia).

To a suspension of 2.16 g (0.01 mol) of 3-cyano-7, 7-dimethyl-5, 6, 7, 8-tetrahydroquinoline-2.5 in 14 ml of glacial acetic acid is gradually added 2.16 g (0.02 mol) of phenylhydrazine. The mixture is stirred for 30 min at boiling of the reaction mass is cooled. The precipitation is filtered off, washed ox-5, 6, 7, 8-tetrahydropyridine is 2.5, so pl. > 300about(decomp) (DMF), M+306.

Found, % : C To 70.7; H 6,0; N 18,0.

C18H18N4O.

Calculated, % : C 70,6; H 5,9; N 18,3.

Proceeding from the appropriate starting compounds II and III, under conditions analogous to example 1 receive:

5-phenylhydrazone 3-cyano-5, 6, 7, 8-tetrahydroquinoline-2,5 (IB);

5-pentacarbonyliron 3-cyano-5, 6, 7, 8-tetrahydroquinoline-2,5 (IB);

5-phenylhydrazone 3-cyano-7-phenyl-5, 6, 7, 8-tetrahydroquinoline-2,5 (Iك);

5-phenylhydrazone 3-urea-7, 7-dimethyl-5, 6, 7, 8-tetrahydroquinoline-2,5 (Ia);

5-phenylhydrazone 3-urea-5, 6, 7, 8-tetrahydroquinoline-2,5 (S).

Physical constants, reaction conditions, yields and analytical characteristics of the claimed compounds (IB-e) are shown in table. 1, and the spectral data in the table. 2.

The biological part.

The study cardiotonic activity of the proposed compounds were carried out on the following sites:

in isolated spontaneously shrinking right Atria of Guinea pigs [8] ;

in awake rats, the effect on the modified index Vergata by known methods [9] .

Compounds of General f is ulitity of the study are presented in Fig. 1 and table. 3.

As can be seen from the table. 3, the positive inotropic activity (figure EC50) on isolated right Atria of Guinea pigs all the claimed compounds significantly superior to known drug million.

The most active of them turned out to be the connection 1-g (EC50- of 5.89 10-10mol). According to the acute toxicity of all compounds belong to the group of low-toxic substances [10] (LD501000 mg/kg orally), with one of them-IB has LD50200 mg/kg, suggesting that this compound has a greater breadth of therapeutic action compared to other claimed compounds. In addition, these experiments showed that compound IB causes the greatest increase in the amplitude of heart contractions compared with milrinone and the rest of the claimed compounds (Fig. 1).

Having considered the above survey data connection IB selected for more in-depth study, which was conducted on the left Atria of Guinea pigs with the imposed rhythm and in the conditions of the whole organism - the waking of normal rats and rats with cobalt cardiomyopathy.

The results of studies on the left atrial IB showed much higher activity, than million (EC50IB - 1,64 10-8mol, EC50million - 1,4 10-7mol).

The study of the cardioprotective activity of compounds IB in awake rats.

Object and methods of research.

Work carried out on conscious normal rats and rats with cobalt cardiomyopathy. Cobalt cardiomyopathy caused by drinking rats solution of cobalt sulfate (1 mg/ml) for 3 months.

Animals previously implanted catheter in the left ventricle, the aorta and jugular vein. Left ventricular (LG) and aortic pressure (BP) were recorded using electromanometer. Curves LG and HELL were analyzed using the program for processing physiological signals in real-time BEAT microcomputer Zabtam 3015. For the evaluation of cardioprotective activity of the test compounds was used the modified index Vergata.

Compound IB was administered intravenously in doses from 5 mg to 50 mg per 1 kg of body weight. Drug comparison of milrinone (Sterling-Wintrop, USA) wedelia in doses of from 3 to 1000 μg/kg

The results of the study

The control rats threshold dose cardiostimulator effect for milrinone was 8 µg/kg, the maximum effect of viewless zavisimoe cardiostimulatory and hypotensive effect: the threshold dose cardiostimulator actions amounted to an average of 15 4 ng/kg, the maximum increase of the index of left ventricular contractility (dp/dt/Pd) was detected in a dose of 3 0.5 μg/kg; the large doses of the drug caused an increase in the duration of the effect.

ED50for an index of contractility (p/dt/Pd) 196 8.3 ng/kg, which is approximately 200 times less than milrinone (P < 0,001).

In rats with cobalt cardiomyopathy differences in cardiotropic activity of the two compounds has increased.

Thus, the claimed connection - connection for the first time found in the quinoline series, namely 5-arylhydrazones 3, 7-substituted-5, 6, 7, 8-tetrahydroquinoline-2,5 General formula 1 possess cardiotonic activity, and higher than a known drug cardiotonic action million.

The data presented indicate that the compounds of General formula I are of interest in terms of finding potential highly effective cardiovascular drugs in the above series of compounds. (56) 1. osti L. , P. Schenone , Menozzi g - Reaction of 2-Dimehylaminomethylene-1,3-diones with Dinucleophyles. V. Synthesis of 5-Acyl-1, 2-dihydro-2-oxo-3-pyridinocarbonitriles and 1, 2, 5, 6, 7, 8-Hexahydro-2,5-dioxo-3-qyinolinecarboxamides - J. Heter. Chem. , 1985, 22 (6), 1503-1509.

2. H. Junek , Wolfbeis O. S. , Sprintschnik H. , Wolny H. - Synthesen von Alkyl-bzw. Cycloalkylpyridinen und Naphthyridinen. B/P> 4. Pat. 4276293, 1981 USA / Chem Abstr. 1981, v 95, n 2039482 z.

5. Pat. 4305948, 1982 USA / hem. Abstr. 1982, v. 96 N 122642 p.

6. Jonnd R. A. , Ward A. - Milrinone A preliminary review of its pharmacologycal properties and therapeutic'yse-Drugs, 1988, 36, 158-192.

7. Kitaev Y. P. , Busygin B. N. - Hydrazones, Moscow, "Nauka", 1974.

8. San Feliciano , A., M. Medarde , E. Caballero et al. - Synthesis and Evaluation of Cardiotonic Activity of Simple Butenolides. - Eur. J. Med. Chem. , 1990, 25, 413-417.

9. Medvedev O. S. , Proshkin S. D. , A. V. Savchenko et. al. - BEAT - a system for multicannel processing of physiological signals in real time - Proceeding of the ISMM International Symposium: Mini and Microcomputers and their applications, Lugano, Switzerland, June 19-21, 1990, 29-31.

10. Sanotski I. C. - Methods for determining the toxicity and hazards of chemicals, M. : Medicine, 1970.

Arylhydrazones 5,6,7,8-tetrahydroquinoline-2,5 General formula

< / BR>
where X is a CN - group;

R1and R2-CH3, R3-C6H5;

R1and R2-H, R3-C6H5;

R1and R2-H, R3-C6F5;

R1-H, R2and R3-C6H5< / BR>
if X is - CONH2group,

R1and R2- CH3, R3-C6H5,

R1and R2-H, R3-C6H5,

having cardiotonic activity.

 

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32 cl, 1 tbl, 132 ex

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EFFECT: obtaining novel biologically active compounds, possessing properties which open calcium-activated potassium channels of high conductivity.

12 cl, 6 ex, 2 tbl, 7 dwg

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